Functional protection by acute phase proteins α1-acid glycoprotein and α1-antitrypsin against ischemia/reperfusion injury by preventing apoptosis and inflammation
Functional protection by acute phase proteins α1-acid glycoprotein and α1-antitrypsin against ischemia/reperfusion injury by preventing apoptosis and inflammation
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DOI：
10.1161/01.cir.102.12.1420
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发表时间：
2000-09-19
期刊：
影响因子：
37.8
通讯作者：
Buurman, WA
中科院分区：
文献类型：
--
作者：
Daemen, MARC;Heemskerk, VH;Buurman, WA
背景缺血再灌注（I/R）引起细胞凋亡、炎症和组织损伤，导致器官功能障碍。缺血预处理可以预防这种损伤。本研究探讨了急性期蛋白α(1)-酸性糖蛋白（AGP）和α(1)-抗胰蛋白酶（AAT）在肾脏缺血预处理中的保护作用。方法与结果：外源性AGP和AAT可抑制小鼠肾损伤45分钟后的细胞凋亡和炎症反应。通过核小体间DNA切割、末端脱氧核苷酸转移酶介导的dUTP缺口末端标记以及肾脏caspase-1-和caspase-3样活性的测定来评估，再灌注时给予AGP和AAT可在2小时和24小时阻止细胞凋亡。AGP和AAT具有抗炎作用，表现为24h后肾肿瘤坏死因子- α表达和中性粒细胞内流降低。总的来说，这些药物可以改善肾功能。再灌注后2小时给予AGP和AAT时，观察到类似的效果，但程度较轻，没有功能改善。此外，I/R引起急性期反应，反映在24小时后血清AGP和血清淀粉样蛋白P （SAP）水平升高，肾再灌注18小时后肝脏急性期蛋白mRNA水平升高。结论：我们认为AGP和AAT的抗凋亡和抗炎作用有助于与缺血预处理和其他损伤相关的延迟型保护。这一机制可能与许多与I/R损伤相关的临床状况有关。此外，外源性给药这些蛋白质可能提供新的治疗手段。
Background-Ischemia followed by reperfusion (I/R) causes apoptosis, inflammation, and tissue damage leading to organ malfunction. Ischemic preconditioning can protect against such injury. This study investigates the contribution of the acute phase proteins alpha(1)-acid glycoprotein (AGP) and alpha(1)-antitrypsin (AAT) to the protective effect of ischemic preconditioning in the kidney.Methods and Results-Exogenous AGP and AAT inhibited apoptosis and inflammation after 45 minutes of renal VR in a murine model. AGP and AAT administered at reperfusion prevented apoptosis at 2 hours and 24 hours, as evaluated by the presence of internucleosomal DNA cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, and the determination of renal caspase-1- and caspase-3-like activity. AGP and AAT exerted anti-inflammatory effects, as reflected by reduced renal tumor necrosis factor-alpha expression and neutrophil influx after 24 hours. In general, these agents improved renal function. Similar effects were observed when AGP and AAT were administered 2 hours after reperfusion but to a lesser extent and without functional improvement. Moreover, I/R elicited an acute phase response, as reflected by elevated serum AGP and serum amyloid P (SAP) levels after 24 hours, and increased hepatic acute phase protein mRNA levels after 18 hours of renal reperfusion.Conclusions-We propose that the antiapoptotic and anti-inflammatory effects of AGP and AAT contribute to the delayed type of protection associated with ischemic preconditioning and other insults. This mechanism is potentially involved in the course of many clinical conditions associated with I/R injury. Moreover, exogenous administration of these proteins may provide new therapeutic means of treatment.